1. Medical Cannabis: An overview
Clinical Prof Nicholas Lintzeris MBBS, PhD, FAChAM
Director D&A Services, SESLHD
Lambert Initiative in Cannabinoid Therapeutics, University Sydney

2. Overview of presentation
History of medical cannabis
Understanding the cannabinoids: what are they and how do they work?
Evidence for medical cannabinoids
Medical cannabis in Australia today

3. Galen: greek physician prescribed cannabis 150 AD
William Oshaunnessy: Irish physician in Br East India company: documented medical cannabis use in India
Hua Tuo: Han dynasty: 2nd century AD: first anaesthetic for surgery: combination of cannabis and wine.

4. History of medical cannabis
>2000 years of therapeutic use
As late as 19th century, cannabis preparations widely prescribed by ‘Western’ doctors.
bronchitis, epilepsy, burns, hypnotic, analgesia, PMS
Prohibition since early 20th Century led to abandonment of cannabis as therapeutic agent
Interest rekindled since 1980’s
Consumer advocacy
Scientific developments

5. Varieties of Cannabinoids
Endocannabinoids
Phytocannabinoids
Synthetic
cannabinoids
In your brain and body
In plants
From the lab
Anandamide, 2-AG, Noladin ether
etc.
THC, CBD, CBG, CBDV, THCV, CBC, CBN, THCVA
etc.
Nabilone, HU-210, AB-PINACA, JWH-018,
etc

6. Brain regions that express the CB1 cannabinoid receptor
Red = abundant CB1 receptor expression Black = moderately abundant CB1 receptor expression
Brain Regions That Express the CB1 Receptor
CB1 receptors are among the most abundant G protein–coupled receptors in the brain, present in almost every brain region and on many different types of neurons. CB1 receptors are particularly abundant in brain regions such as the hippocampus, cortex, cerebellum, and basal ganglia
The study of the ECS in these brain areas has implicated this system in modulating motor function in the cerebellum and basal ganglia. In the hippocampus, the ECS plays a role in pathways related to learning and memory, and in the cerebral cortex the system is implicated in cognitive information processing. In the amygdala the ECS modulates emotionality and in the brain stem and spinal cord the ECS is involved in nociception Furthermore, studies of CB1 receptors within the mesolimbic dopaminergic system indicate that the ECS plays a role in reward and motivational processes. Finally, it is now clear that the ECS directly modulates the activity of neuronal circuits regulating food intake, both within the hypothalamus and the limbic system
The density of CB1 receptors in different brain areas is similar to levels of -aminobutyric acid (GABA)- and glutamate-gated ion channels
An important role for CB1 receptors in the brain is to mediate retrograde signaling. This is defined as the communication by signaling molecules (in this case, endocannabinoids) derived from postsynaptic cells that diffuse to presynaptic cells
Joy JE, Watson SJ, Benson JA, Institute of Medicine (US). Division of Neuroscience and Behavioral Health. Marijuana and Medicine: Assessing the Science Base. Washington, DC: National Academy Press; Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47(suppl 1): Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58: Fernandez-Ruiz J, Gonzales S. Cannabinoid control of motor function at the basal ganglia. Handb Exp Pharmacol. 2005: Rodriguez de Fonseca F, Del Arco I, Martin-Calderon JL, Gorriti MA, Navarro M. Role of the endogenous cannabinoid system in the regulation of motor activity. Neurobiol Dis. 1998;5(6 Pt B): Lutz B. The endocannabinoid system and extinction learning. Mol Neurobiol. 2007;36: Egerton A, Allison C, Brett RR, Pratt JA. Cannabinoids and prefrontal cortical function: insights from preclinical studies. Neurosci Biobehav Rev. 2006;30: Solinas M, Justinova Z, Goldberg SR, Tanda G. Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. J Neurochem. 2006;98: Cota D, Woods S. The role of the endocannabinoid system in the regulation of energy homeostasis. Curr Opin Endocrinol Diabetes. 2005;12: Kawamura Y, Fukaya M, Maejima T, et al. The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. J Neurosci. 2006;26: Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain. Science. 2002;296:
Adapted from Joy JE et al, eds. Marijuana and Medicine

7. CB2 Receptors: immune system modulators
CB2 receptors found in spleen, tonsils, thymus gland, bones, skin
Localised in monocytes, macrophages, B-cells and T-cells
Limited CB2 in brain, except in inflammatory states (microglia)
Stimulation of CB2 can reduce inflammation and neuropathic pain
Cannabinoid Receptors
Cannabinoid receptors are G protein–coupled receptors consisting of 7 transmembrane-spanning domains
The CB1 receptor is among the most abundant G protein–coupled receptors in the brain, present in almost every brain region and on many different types of neurons
CB1 receptors receptors are also located in a variety of peripheral tissues such as adipose tissue, liver, muscle, the GI tract, and pancreas
Howlett AC, Barth F, Bonner TI, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54:
Devane WA et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:
Munro S et al. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61-65.
Ameri A. The effects of cannabinoids on the brain. Prog Neurobiol. 1999;58:
Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:
Cota D, Woods SC. The role of the endocannabinoid system in the regulation of energy homeostasis. Curr Opin Endocrinol Diabetes. 2005;12:

8. Varieties of Cannabinoids
Endocannabinoids
Phytocannabinoids
Synthetic
cannabinoids
In your brain and body
In plants
From the lab
Anandamide, 2-AG, Noladin ether
etc.
THC, CBD, CBG, CBDV, THCV, CBC, CBN, THCVA
etc.
Nabilone, HU-210, AB-PINACA, JWH-018,
etc

9. >100 cannabinoids in the plant. Most are non-psychoactive.
Each has its own pharmacological actions and therapeutic potential.
“Entourage” effects

10. Potency of NSW police seized cannabis: high THC and low CBD Swift et al PLoS One 2013- A O L 5 1 2 3 4 % N E % C O N T E B D - A o t a l 5 1 2 3 4
Average THC content = 15%
85% of samples contained <0.1% CBD-tot
CBD uniformly low on the most part
THC: psychoactive, sedation, analgesia, antiemesis, antispasmodic
CBD: not psychoactive, anxiolytic, antipsychotic, anticonvulsant

11. Cannabidiol (CBD) modulates many of the effects of THC in cannabis
THC and CBD =
THC only =

12. Potential adverse events of cannabis
Cognition
Cannabis use associated with mild cognitive impairments in attention, memory, learning, psychomotor functions
Most effects reversible with abstinence, although may persist in people with early & heavy adolescent use
Mental health
Adolescent cannabis use associated with increased anxiety
Increased risk of psychoses OR = 2.09 (95%CI 1.54 to 2.84) & linked to genetic predisposition
Dependence: estimated at 1 in 10 illicit users
Physical effects
Hypotension, tachycardia, dizziness, dry mouth

13. Preclinical research identifies a range of possible therapeutic effects from phytocannabinoids

14. Systematic review Cannabinoids Whiting et al JAMA June 2015
Condition
# studies
Conclusion
Nausea & vomiting
3 RCTs
THC or THC/CBD > placebo
Weight gain in HIV/AIDS
1 RCT
THC > placebo
Spasticity in MS / paraplegia
14 RCTs
THC/CBD > placebo
Depression
Placebo > THC/CBD
Anxiety
CBD>placebo
Sleep
12 RCTs
THC/CBD, THC > Placebo
Psychosis
CBD = amisulpiride
Tourette Syndrome
Glaucoma
THC=CBD=placebo
Epilepsy
Not completed
CBD

15. Cannabinoids in chronic pain Systematic review: Whiting et al JAMA June 2015

16. Conditions treated with cannabis (medical marijuana.com)
Acute Gastritis; Adenomyosis; Alzheimer’s; Amyloidosis; Amyotrophic Lateral Sclerosis (ALS); Anaphylactic or Reaction; Angelman Syndrome; Anorexia; Arthritis; Arthropathy (Gout); Asperger Disorder; Asthma; Attention Deficit Disorder (ADD); Autism
Back Pain; Bell's Palsy; Bipolar Disorder; Bruxism; Bulemia
Cachexia; Cancer; Carpal Tunnel Syndrome; Cerebral Aneurysm; CFS; Chronic Pain; Cluster Headaches; CMT Disease; Colitis; Colitis/Ulcerative Colitis; Colon Diverticulitis; Crohn's disease; CVS; Cystic Fibrosis; Cystitis/Urethritis;
Darier's Disease; Depression; Diabetes; Diarrhea; Dravet Syndrome; Dupuytren's Contracture; Dyspepsia; Dystonia
E. T.; Eczema; Ehlers Danlos; Emphysema; Endometriosis; Epilepsy/Seizure Disorder
Felty's syndrome; Fibromyalgia; Friedreich's Ataxia
GastroEsophgeal Reflux Disease; Glaucoma; Graves' disease
Hemophilia A; Henoch-Schonlein Purpura; Herpes; HIV / AIDS; Hydrocephalus; Hypertension (High Blood Pressure); Hyperventilation; HYPOGLYCEMIA-MMj Treatment
Incontinence; Inflammatory Bowel ; Insomnia; Interstitial Pneumonia; Irritable Bowel Syndrome
Limbic Rage Syndrome; Liver Disease; Lupus; Lyme Disease;
Macular Degeneration; Marfan Syndrome-; mastocytosis; MD; Medical Marijuana as Pain Treatment for Patellofemoral Pain Syndrome; Medical Marijuana Treatment for Addiction; Melorheostosis; Meniere's Disease; Menopausal Syndrome; Migraines; Motion Sickness; Movement Disorders; MRSA; Multiple Sclerosis (MS); Muscle Spasm; Muscle Spasms; Myofascial Pain
Nausea; Nephritis; Neurodegenerative Disorders; Neurofibromatosis; Neuropathy; Nightmares; NPS
Osgood-Schlatter; Osteogenesis imperfecta;
Palmar Hyperhydrosis; Pancreatic Cancer; Pancreatitis; Panic Attacks; Panic Disorder; Pectus carinatum (Pigeon breast/chest); Pemphigus; Peptic Ulcer; Peutz-Jehgers; Polyarteritis Nodosa; Polycythemia vera; Porphyria—Alternative Symptom Treatments; Post Concussion Syndrome; Post Traumatic Stress Disorder; PPS-Post Polio Syndrome; Prostate Cancer; Pruritus
Psoriasis; Pylorospasm reflux
Radiation Therapy; Raynaud's phenomenon; Reactive Arthritis; RLS-MMj Treats Symptoms
SAD; Schizophrenia(s); Scleroderma; Scoliosis; Selectivemutism; Shingles; Sinusitis; Sjogren's Syndrome; Sleep Apnea; Spina Bifida and Medical Marijuana; Sturge-Weber; Syringomyelia
Tenosynovitis; Testicular Cancer; Testicular Torsion; Thoracic Outlet Syndrome; Tic Douloureux; Tietze’s Syndrome; Tinnitus; Tourette Syndrome and Cannabinoids; TTM
Wolff-Parkinson-White Syndrome

17. Summary of evidence Historical records
Animal data shows therapeutic potential
Anecdotal reports & case studies of patient benefit (& harms)
Psychopharmacology studies in humans showing some therapeutic potential
Few RCTs conducted, and the majority with pharmaceutical cannabinoids
Strong consumer demand for making cannabis available for medical use

18. Cannabinoid medications licensed internationally
Route
Indication
Nabiximols (Sativex®)
Plant extracted THC:CBD (1:1)
Buccal / SL spray
MS spasticity
Dronabinol (Marinol®)
Synthetic THC
Oral
Anorexia in AIDS, cancer; CINV
Nabilone (Cessamet®)
CINV
CBD (Epidolex®)
Plant extracted CBD
Nil yet
Cannabis plant matter
Various % THC, CBD available
Vaporised
Range of conditions in Holland, Israel, Canada

19. Vaporising cannabis Similar to ‘e-cigarrettes’
Vaporising heats cannabis at lower temperature than ‘smoking’. Higher bioavailability.
No side stream smoke (fewer concerns re: passive smoking)
Peak THC effects: typically min after dose, psychoactive effects for 2-3 hours

20. The United States of Marijuana

21. Colorado dispensary

22. ‘Medical cannabis’ in Australia today
Only illicit cannabis products
Home grown, ‘Street’ supplies, artisanal growers, imported
First legal framework (for terminal illness only) Dec 2014
Swift et al 2005: surveyed 147 medical cannabis users
Chronic pain 57%, depression 56%, arthritis 35%, nausea 27%
Degenhardt et al 2014: 1500 CNMP patients
6.3% CNMP used cannabis past month for pain
Analgesic effects rated as good as / better than opioids
25% subjects said they would use cannabis if they could!
Paediatric epilepsy:
a number of ‘artisanal’ products illegally available in Australia
CBD rich hemp products imported from USA / EU

23. Implications for clinicians today
Use of illicit cannabis for ‘medical’ purposes is common in some areas of medicine.
Most patients will not disclose & most doctors won’t ask
Medical cannabis to become more common in Australia
Increasing advocacy despite unclear evidence of efficacy for most conditions
What role for health providers?
Need for better understanding and education of health providers of the potential harms and therapeutic roles of cannabinoids.